Preclinical efficacy of sepantronium bromide (YM155) in multiple myeloma is conferred by down regulation of Mcl-1

// Verena Wagner 1,* , Dirk Hose 2,3,* , Anja Seckinger 2 , Ludmila Weiz 1 , Tobias Meißner 2 , Thiery Rème 4 , Iris Breitkreutz 1,3 , Klaus Podar 3 , Anthony D. Ho 2 , Hartmut Goldschmidt 2,3 , Alwin Krämer 5 , Bernard Klein 4,6 and Marc S. Raab 1,2 1 Max-Eder Group Experimental Therapies for Hematologic Malignancies, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany 2 Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany 3 National Center of Tumor Diseases, University of Heidelberg, Heidelberg, Germany 4 INSERM U1040, Montpellier, France 5 Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany 6 CHU Montpellier, Institute of Research in Biotherapy, Montpellier, France * These authors contributed equally to this work Correspondence: Marc S. Raab, email: // Keywords : apoptotic signaling, Mcl-1, multiple myeloma, survivin Received : July 15, 2014 Accepted : September 25, 2014 Published : September 26, 2014 Abstract The inhibitor-of-apoptosis family member survivin has been reported to inhibit apoptosis and regulate mitosis and cytokinesis. In multiple myeloma, survivin has been described to be involved in downstream sequelae of various therapeutic agents. We assessed 1093 samples from previously untreated patients, including two independent cohorts of 392 and 701 patients, respectively. Survivin expression was associated with cell proliferation, adverse prognostic markers, and inferior event-free and overall survival, supporting the evaluation of survivin as a therapeutic target in myeloma. The small molecule suppressant of survivin - YM155 - is in clinical development for the treatment of solid tumors. YM155 potently inhibited proliferation and induced apoptosis in primary myeloma cells and cell lines. Gene expression and protein profiling revealed the critical roles of IL6/STAT3-signaling and the unfolded protein response in the efficacy of YM155. Both pathways converged to down regulate anti-apoptotic Mcl-1 in myeloma cells. Conversely, growth inhibition and apoptotic cell death by YM155 was rescued by ectopic expression of Mcl-1 but not survivin, identifying Mcl-1 as the pivotal downstream target of YM155 in multiple myeloma. Mcl-1 expression was likewise associated with adverse prognostic markers, and inferior survival. Our results strongly support the clinical evaluation of YM155 in patients with multiple myeloma.